Rapid integrity testing of porous materials

ABSTRACT

The invention relates to a rapid recirculation based integrity testing of porous material and to an apparatus and system for performing the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Patent Application of U.S. applicationSer. No. 11/599,501, filed on Nov. 14, 2006, projected U.S. Pat. No.7,587,927 projected Issue Date: Sep. 15, 2009, the entire contents ofwhich are incorporated by reference herein.

FIELD OF THE INVENTION

The invention relates generally to the field of validation testing. Inspecific embodiments the invention relates to integrity testing ofporous materials.

BACKGROUND OF THE INVENTION

Porous materials play a significant role in a wide variety of industrialapplications including processing, e.g. filtering, packaging,containing, and transporting manufactured goods and raw materials. Theindustrial settings in which they are used include the pharmaceuticaland biotechnology industries; the oil and gas industries and the foodprocessing and packaging industries, to name but a few.

In several of these industries such as the pharmaceutical andbiotechnology industries and the food processing industry porousmaterials, e.g. membranes, may be used as filtration devices toeliminate undesirable and potentially harmful contaminants frommarketable end products. Quality control and quality assurance requiresthat these filtration devices comply with desired performance criteria.Integrity testing provides a means for ensuring that a particular devicemeets its desired performance criteria. Typically, in the case ofmembranes, integrity testing ensures that the membrane is free ofdefects, e.g. breaches in the membrane exceeding a desired sizelimitation, which would impair the membrane function and thus allow theend product to become contaminated with harmful or undesirable material.

A variety of integrity tests suitable for ensuring the performancecriteria of membranes, e.g., filtration devices, have been previouslydescribed. These include the particle challenge test, the liquid-liquidporometry test, bubble point test, the air-water diffusion test anddiffusion tests measuring tracer components (see, e.g., U.S. Pat. Nos.6,983,505; 6,568,282; 5,457,986; 5,282,380; 5,581,017; Phillips andDileo, 1996, Biologicals 24:243; Knight and Badenhop, 1990, 8^(th)Annual Membrane Planning Conference, Newton , Mass.; Badenhop; Meltzerand Jorritz, 1998, Filtration in the Biopharmaceutical Industry, MarcelDekkar, Inc., New York, N.Y.). A number of devices suitable for testingthe integrity of a membrane have also been described (see, e.g., U.S.Pat. Nos.: 4,701,861; 6,907,770; 4,881,176).

The previously described integrity tests have significant shortcomings.The particle challenge test, for example, is destructive and thus canonly be performed once on a given specimen. Although it can be used forpost-use integrity testing, it is not suitable for pre-use validation,except for validating the performance of a production lot. Lotvalidation, however, provides little assurance regarding the integrityof individual membranes within a production lot. Moreover, the testprocedures and analysis can be difficult and complex.

Flow based tests provide one method of integrity testing porousmaterials that does not require the destruction of the sample. Thisallows for the repeated testing of individual samples. Testing may beconducted prior to use or after one or more uses. Flow based tests may,however, be limited in their sensitivity, e.g. size detection limit ofmembrane defects. A further limitation of certain flow based tests istheir reliance on detection methods which may be unduly cumbersome.Moreover, some flow based tests require the system to equilibrate to asteady state before integrity testing may begin. These tests arerelatively slow and inefficient in their consumption of expensive andenvironmentally unfriendly reagents.

A need therefore exists for an integrity test that is suitable for anyporous material, including, for example, both single layered andmulti-layered devices, e.g. devices comprised of membranes. The testshould be fast, sensitive, non-destructive, inexpensive and easy toexecute. Moreover, the test should minimize the use of expensivereagents. It would also be useful to be able to characterize a defect,e.g. by size or density, to determine if a desired performance criteriaof the porous material has been compromised as a result of the defect orif the defect is inconsequential in terms of performance criteria. Aneed also exists for an apparatus and system which can implement such atest. Various embodiments of the invention disclosed herein meet theserequirements.

SUMMARY OF THE INVENTION

Certain embodiments of the invention provide a method, for evaluatingthe integrity of a porous material that is fast, sensitive,reproducible, non-destructive, inexpensive, flexible in terms of theorientation of the porous material, amenable to a wide variety of signaldetection means and easy to execute. The porous material may comprise asingle layered or multi-layered membrane device. Thus in someembodiments the invention provides a method of integrity testing ofporous materials that is based on the concentration of one or moredetectable substances, e.g. one or more gases, in the permeate of aporous material, such as a membrane. In certain embodiments the test maybe a binary gas test, i.e. dependent on two gases, however, more than 2gases are contemplated as are other detectable substances, e.g., one ormore liquids. Other embodiments of the invention provide a method forcharacterizing a defect in a porous material, e.g. by size or density,to determine if a desired performance criteria of the porous materialhas been compromised as a result of the defect or if the defect isinconsequential in terms of performance criteria. Still otherembodiments provide an apparatus and system which can implement theseintegrity tests.

In one embodiment the invention provides a method of assessing theintegrity of a porous material comprising a) wetting the porous materialwith a liquid; b) contacting a first surface of porous material with amixture comprising a carrier and a detectable substance; c) applyingpressure to the first surface of the porous material such that at leastsome of the carrier and the detectable substance permeate the porousmaterial; d) recirculating the mixture of b) from a permeate of theporous material in a fixed volume on the permeate side while continuingto apply the pressure of c); e) assessing the concentration of thedetectable substance in the permeate of the porous material in a fixedvolume over time. The test may optionally comprise an additional step f)comparing the assessed concentration in e) with the concentration of thedetectable substance in a permeate of an integral porous material,wherein an assessed concentration in e) which is greater than theconcentration of the detectable substance in a permeate of the integralporous material indicates the porous material is not integral. Integral,when referring herein to a porous material, means non-defective.

In another embodiment the invention provides a method of assessing theintegrity of a porous membrane comprising a) wetting the porous materialwith a liquid b) contacting a first surface of the porous material withcompressed air; and with a fluoro-carbon such that a mixture is formedcomprising the compressed air and the fluoro-carbon; c) applyingpressure to the first surface of the porous material such that at leastsome of the carrier and the detectable substance permeate the porousmaterial; d) recirculating the mixture of b) from a permeate of theporous material in a fixed volume on the permeate side while continuingto apply the pressure of c); e) assessing the concentration of thefluoro-carbon in the permeate of the porous material over time; and f)comparing the assessed concentration in e) with the concentration of thefluoro-carbon in a permeate of an integral porous material submitted tothe same conditions over time, wherein an assessed concentration in e)which is greater than the concentration of the fluoro-carbon in apermeate of the integral porous material indicates the porous materialis not integral.

In still another embodiment the invention provides a method of assessingthe size of a defect in a sample porous material comprising a) wettingthe porous material with a liquid; b) contacting a first surface ofporous material with a mixture comprising a carrier and a detectablesubstance; c) applying pressure to the first surface of the porousmaterial such that at least some of the carrier and the detectablesubstance permeates the porous material; d) recirculating the carrierand detectable substance found in a permeate of the porous material in afixed volume on the permeate side while continuing to apply the pressureof (c); e) assessing the concentration of the detectable substance inthe permeate of the porous material over time; and f) comparing theassessed concentration in e) with the concentration over time of thedetectable substance in a permeate of one or more standard porousmaterials, wherein each of said one or more standard porous materialscomprises a defect of known size and is submitted to the same testconditions as the sample porous material, thereby determining the sizeof the defect.

In a further embodiment the invention provides a method ofcharacterizing a defect in a sample porous material comprising a)wetting the porous material with a liquid; b) contacting a first surfaceof porous material with a mixture comprising a carrier and a detectablesubstance; c) applying pressure to the first surface of the porousmaterial such that at least some of the carrier and the detectablesubstance permeates the porous material; d) recirculating the carrierand detectable substance found in a permeate of the porous material in afixed volume on the permeate side while continuing to apply the pressureof (c); e) assessing the concentration of the detectable substance inthe permeate of the porous material over time; and f) comparing theassessed concentration in e) with a calculated theoretical concentrationof the detectable substance in the permeate of one or more knownstandard porous materials comprising a defect of a predetermined size.

The skilled artisan will understand that one or more of the stepsrecited in each of the methods described above may be combined into asingle step.

In yet another embodiment the invention provides an apparatus forassessing the integrity of a sample porous material comprising a) ahousing suitable for receiving a porous material to be integrity tested;b) a source of a detectable substance in fluid communication with thehousing; c) a source of a carrier for the detectable substance in fluidcommunication with the housing; d) a detector for detecting thedetectable substance; e) a recirculation pump in communication with thedetector and the housing for containing the porous material; and f) asource of an external force.

In still other embodiments the invention provides a system for assessingthe integrity of a sample porous material comprising an apparatussuitable for assessing the integrity of a porous material and aprogrammable logic controller suitable for receiving input from a user.

Additional objects and advantages of the invention will be set forth inpart in the description which follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theobjects and advantages of the invention will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a is a schematic of an apparatus used to test the integrity ofmembrane cartridges according to one embodiment of the invention; FIG. 1b is a first cross section of an apparatus housing and a samplemembrane; FIG. 1 c is a second cross section of an apparatus housing anda sample membrane, FIG. 1 d is a side view of the housing and samplemembrane.

FIG. 2 is a graph showing a comparison of Fourier Transform InfraredSpectroscopy (FTIR) signal in membrane cartridges having different sizedefects.

FIG. 3 is graph showing a comparison between theoretically calculatedand experimentally observed permeate concentration for membranecartridges having a defect of known size.

FIG. 4 a is a graph showing Freon signal versus time for a sampling ofin process membrane sub assemblies.

FIG. 4 b is a graph showing Freon signal versus time for the samepopulation of membranes described in 4 a after further processing.

FIG. 5 is a graph showing the results of ten replicate tests of a knowngood cartridge installed with a 1.31 micron fixed orifice defect versusresults for the same cartridge before creation of the defect.

FIG. 6 is a graph showing the results of an integrity test on severalasymmetric PES membrane cartridges under non-optimized conditions(forward) (15.5 psig partial pressure of freon and a total contact side(i.e. non-permeate side) pressure of 46 psig). Orifice refers to a fixeddefect of known size. Cartridge 0620, although not having a createdorifice, was a known defective cartridge.

FIG. 7 is a graph comparing results of an integrity test of someasymmetric PES membrane cartridges from FIG. 6 run under optimized(reverse) and non-optimized (forward) conditions(a freon partialpressure of 11.25 psig and a total contact side (i.e. non-permeate side)pressure of 30 psig). Orifice refers to a fixed defect of known size.

DESCRIPTION OF THE EMBODIMENTS Methods of the Invention

Certain embodiments of the invention provide a method, for assessing theintegrity of a porous material. Typically the downstream side volume orpermeate volume may remain relatively invariant. Moreover if thedownstream volume is known and the diffusional flow through an integralmembrane is known, or insignificant compared to the defect flow, theeffective defect size may be determined from the rate of rise of theconcentration of the detectable substance in the permeate. The test thusrelies on measuring the concentration of at least one detectablesubstance, such as a gas or vapor in the permeate of a porous materialas a function of time and then correlating that concentration with aknown or predetermined value for an integral porous material such as amembrane and or alternatively for a porous material having a defect ofknown size, e.g. diameter. The detectable substance may be recirculatedto present a uniform permeate sample to the detector. Recirculation maybe accomplished using a pump in communication with the permeate side ofthe porous material being tested for integrity. In certain embodimentsthe benefits of recirculation may be both economical and environmentalin that it limits amount of reagents used. The recirculation rate may beadjusted such that the detectable substance is quickly incorporated intothe stream flowing to the detector. Recirculation eliminates the need toachieve a steady state and thus may provide a more rapid result comparedto previously described integrity tests. Moreover, the method may beeasily adapted to accommodate virtually any type of detector known inthe art and thus in certain embodiments the invention may avoid the useof cumbersome detection means requiring a direct line of sight, e.g., aphoto acoustic detector. The method may allow for detection of smallerdefects compared to previously described techniques. The method ishighly reproducible and in embodiments where the porous material is amembrane, the method permits testing the integrity of a membrane in anyorientation. Thus, for example, an asymmetric membrane may be contactedwith the mixture of the carrier and the detectable substance either fromthe tight surface where pore size is smaller, or the open surface wherepore size is larger. Similarly the permeate which is fed to the detectormay come from either side of the membrane, so long as it is opposite theside initially contacted with the mixture. Thus a membrane may beintegrity tested from either orientation without the need to physicallyreorient the membrane. Both sides of the porous material being testedmay be evacuated by means of one or more exhaust conduits in fluidcommunication with each side of the porous material thus facilitatingremoval of the detectable substance after each test thereby reducingbackground of subsequent tests and increasing sensitivity.

The steady state diffusion equation provides a flow rate that is themaximum that would be seen if the integrity test described herein wasallowed to equilibrate to steady state. This suggests why a transienttest time, which may be performed quickly, may be well suited fordetermining the integrity of porous materials being tested. If thesystem reaches steady state, diffusion may overcome the convective flowthrough the defect making detection of the detectable substancedifficult if not impossible.

Steady State Gas Diffusion equation (Fick's First Law)

$\begin{matrix}{\mspace{40mu} {Q = {\frac{\rho_{L}}{M_{L}}\frac{D}{H}\frac{\left( {P_{in} - P_{out}} \right)}{L}\frac{{RTA}_{f}ɛ}{P_{out}}}}} & \;\end{matrix}$

where:

-   -   Q=Gas flow (cm³/sec) evaluated at downstream conditions    -   ρ_(L)=Liquid density (g/cm³)    -   M_(L)=Liquid molecular weight (g/mol)    -   D=Diffusivity of the gas through the liquid (cm²/sec)    -   H=Henry's law constant (psi)    -   P_(in)=Absolute upstream pressure (psia)    -   P_(out)=Absolute downstream pressure (psia)    -   L=Membrane thickness (cm)    -   R=Gas constant (1205.95 cm³ psi/mol/K)    -   T=Absolute temperature (K)    -   A_(f)=Total membrane frontal area (cm²)        -   ε=Membrane porosity            Choke flow, which is applicable to a transient test time is            described infra at page 16. In certain embodiments the            integrity test according to the invention may be practiced            without the necessity of allowing the system to reach steady            state, and thus provides for a rapid determination regarding            the integrity of a porous material such as a membrane.

The conditions under which the methods of the invention are practicedmay be chosen by the skilled artisan. As an example, the methods of theinvention may be practiced at a temperature ranging from about 0° C. toabout 100° C., 4° C. to about 60° C., 10° C. to about 50° C., 15° C. toabout 30° C. In one embodiment the invention is practiced at atemperature of about 20° C. In another embodiment the invention may bepracticed at a temperature of about 4° C.

The test may be run under differential pressure that is one side of thesample porous material to be tested may be at a first pressure and asecond side of the sample porous material may be at a second pressure.In certain embodiments at least one side of the porous material is at apressure which may be equal to or near the bubble point of the porousmaterial. Thus the pressure on the feed side of the sample porousmaterial may be greater than the pressure on the permeate side of theporous material.

The methods of the invention may be practiced at a pressure, e.g., afeed pressure, ranging from about 1 PSI to about 100 PSI; from about 10PSI to about 70 PSI; from about 5 PSI to about 60 PSI; from about 20 PSIto about 45 PSI. In another embodiment the methods of the invention maybe practiced at a pressure of about 30-50 PSI. In one embodiment themethods of the invention may be practiced at a pressure of about 50 PSI:In another embodiment the methods of the invention may be practiced at apressure of about 30 PSI. In yet another embodiment the methods of theinvention may be practiced at a pressure of about 15 PSI. In a furtherembodiment the invention may be practiced at a pressure that is justbelow the bubble point of the porous material. In still otherembodiments the pressure may be ramped up, e.g., slowly increased bysmall increments while measuring flow rate and concentration. In yetother embodiments the pressure may be ramped down, e.g., slowlydecreased by small increments while measuring flow rate andconcentration. The pressure may be ramped up or down in stepwiseincrements. The stepwise increments can be between 0.5 psi and 100 psi;or between 1 psi and 25 psi; or preferably between 5 psi and 10 psi. Insome embodiments the test may be run with at least one side of thesample porous material to be tested under vacuum, e.g. at a pressureless than 14.7 psia, less than 5 psia.

In certain embodiments both the carrier and the detectable substance mayboth be a gas. In these embodiments the sensitivity of the test may beas follows. The flux of tracer gas due to diffusion may be timedependent (and equal zero at time=0) while the convective flux mayremain constant once a pressure gradient is established and maintained.Upon pressurizing the upstream side of the membrane, the flux due todiffusion will be zero (but increasing) while the convective flux may befully established. The limitations of sensitivity then become 1) thetime required to present a representative sample to the detector, 2) thedetector sensitivity, and 3) the delay before the diffusive flow becomessignificant compared to the convective flow.

$\frac{y_{Tracer}}{t} = \frac{n_{Tracer}{_{Diffusion}{+ n_{Tracer}}}_{Convection}}{N_{Total}}$

Where:

-   -   y_(Tracer)=Permeate side Tracer gas mole (or volume) fraction    -   n_(Tracer)=molar flux of tracer (moles/second)    -   N_(Total)=total amount of gas in the permeate side volume        (moles)

In some embodiments a detectable substance, e.g., a tracer gas thatreacts with a component of the wetting liquid may be used. For example,the porous material could be wet with an aqueous solution of sodiumhydroxide. The porous material could be contacted with a mixture ofcarbon dioxide (detectable substance) and compressed air (carrier), suchthat any CO₂ which diffuses into the water would react. However, any gaswhich flows through a defect would not react, thus the presence of CO₂on the permeate side would be indicative of a defect. The skilledartisan would understand that the byproducts of the reaction (which inthis case are water soluble) would have to be flushed from the porousmaterial before it is used.

1. Quantifying Defect Size

As discussed above, it may be desirable in certain situations to be ableto characterize a defect or defects in a porous material beyond merelynoting its presence or absence. Certain embodiments of the inventionprovide a method of calculating defect diameter and distributiondensity, both of which may be useful in assessing a material'sintegrity, particularly as it relates to retention. Gas flow through adefect is due to primarily to convective rather than diffusivetransport. Several researchers have modeled gas flow in defects assumingthe Hagen-Poiseuille equation applies. However, one skilled in the artwill recognize that this equation is valid only at the limit of very lowpressure differentials across the membrane (R. Prudhomme, T. Chapman,and J. Bowen, 1986, Applied Scientific Research, 43:67, 1986.). Attypical integrity test conditions, the flow through a defect moreclosely follows choke flow, particularly if the defect diameter is largerelative to the thickness of the retentive zone within the membrane. Ingeneral, the transition from Hagen-Poiseuille flow to turbulent flow tochoke flow is a function of the ratio of the permeate pressure to thefeed pressure. The choke flow equation is provided below and may be usedto calculate the defect diameter assuming a single defect is present:

$\begin{matrix}{\mspace{40mu} {Q = \frac{\frac{N_{p}P_{in}\pi \; d_{p}^{2}}{4}\sqrt{{\frac{\gamma \; M\; w}{R\; T}\left\lbrack \frac{2}{\gamma + 1} \right\rbrack}^{\frac{\gamma + 1}{\gamma - 1}}}}{\rho_{exit}}}} & \;\end{matrix}$ $\begin{matrix}{\mspace{34mu} {\rho_{exit} = \frac{P_{out}M\; w}{R\; T}}} & \;\end{matrix}$

where:

-   -   Q=Gas flow (cm³/sec) evaluated at downstream conditions    -   N_(p)=Number of defects    -   D_(p)=Defect diameter (microns)    -   γ=Ratio of specific heats    -   Mw=Gas molecular weight (g/mole)    -   R=Gas constant (1205.95 cm³ psi/mol/K or 8.314 E+7 g        cm²/mol/K/s²)    -   T=Absolute Temperature (K)    -   P_(in)=Absolute upstream pressure (psia)    -   P_(out)=Absolute downstream pressure (psia)

Porous Materials

The integrity of any porous material may be assessed using the methods,devices and systems of the invention. As an example, but not as alimitation, the porous material may take the form of a cartridge, acassette, a sheet, a column, a chip, a bead, a plate container, abottle, a cap, a cylinder, a tube, a hose, or a monolith.

The porous material may be comprised of an organic or inorganicmolecules or a combination of organic and inorganic molecules. Theporous material may be comprised of a hydrophilic compound, ahydrophobic compound, an oleophobic compound, an oleophilic compound orany combination thereof. The porous material may be comprised of one ormore a polymers or copolymers. The polymers may be crosslinked.

The porous material may be comprised of any suitable material,including, but not limited to polyether sulfone, polyamide, e.g., nylon,cellulose, polytetrafluoroethylene, polysulfone, polyester,polyvinylidene fluoride, polypropylene, a fluorocarbon, e.g. poly(tetrafluoroethylene-co-perfluoro(alkyl vinyl ether)), poly carbonate,polyethylene, glass fiber, polycarbonate, ceramic, and metals. Theporous material may be in the form of a single or multilayered membrane.The porous material may be, for example, a hollow fiber, a tubularformat, a flat plate, or spirally wound.

In certain embodiments the porous material may be a membrane, e.g., afilter or filtration device comprising a membrane. The porous materialmay be capable of excluding solutes based on the size of the solutes. Asan example the pores of the material may be too small to allow thepassage of a particle of a specific size, e.g., diameter or a particularmolecular weight. The membrane may be contained in a housing e.g., acartridge, a cylinder, a cassette. The membrane may be a flat sheet, amulti-layered sheet, a pleated sheet or any combination thereof. Themembrane pore structure may be symmetric or asymmetric. The membrane maybe used for filtration of unwanted materials including contaminants suchas infectious organisms and viruses, as well as environmental toxins andpollutants. The membranes may include ultrafiltration membranes,microfiltration membranes, and reverse osmosis membranes.

Liquids and Wetting Agents

In certain embodiments the porous material may be wetted with one ormore liquids prior to testing. The methods of the invention provide forthe use of any suitable liquid to be used as a wetting agent for theporous material. Selection of a wetting agent is within the skill of theartisan and may be determined based on chemical and physical propertiesof the porous material. Porous materials vary in terms of theirwettability, which is often expressed in terms of the contact angle θ.The methods of the invention, can be adapted for hydrophobic membranes,for example, by selecting non-aqueous solvents or prewetting it with lowsurface tension fluids (such as a mixture of 30% isopropyl alcohol and70% water) and exchanging the low surface tension fluid with water oralternatively wetting the membrane with one or more organic solvents.The operating pressure can be adjusted by selecting fluids with theappropriate surface tension γ, which generally range from about 74dyne/cm for water to about 10 dyne/cm for perfluorinated solvents. Askilled artisan will thus understand that a liquid may be selected byconsidering the chemical properties of the porous material to be tested.As an example, where the porous material is comprised of a hydrophilicmaterial a suitable liquid includes water or a solution comprised ofwater. The solution may be, for example, aqueous solutions containingsalts and oxygenated hydrocarbons such as aldehydes or alcohols or neatalcohols such as isopropyl alcohol. Where the porous material is acomprised of a hydrophobic material a suitable liquid may include anyorganic solvent such as dodecane, perfluorinated compounds, carbontetrafluoride, hexane, acetone, benzene, toluene or the like.

Carriers and Detectable Substances

The carrier and the detectable substance may be chosen by the skilledartisan, based on the solubility of the detectable substance in thecarrier. In some embodiments, it is contemplated that the detectablesubstance may be one or more vapors or liquids. In other embodiments thecarrier and detectable substance may be a mixture of gases and vapors.In other embodiments the carrier and the detectable substance may bothbe gases. Virtually any gas composition may be used in practicing themethods of the invention, provided that the solubilties in the liquidused to wet the porous material are such that the detector is notflooded with the carrier thereby blinding the detector to the presenceof the detectable substance. Typically, the mixture comprising thecarrier and the detectable substance will have a higher concentration ofcarrier than detectable substance.

Where a plurality of gases is used, i.e., where the carrier and thedetectable substance, or substances are all gases, the percentage ofeach gas in the mixture may be chosen by the skilled artisan. As anexample, where 2 gases are used the first gas may be used at apercentage volume ranging from about 0.01% to about 99.99%, and thesecond gas may be present at a percentage volume ranging from about0.01% to about 99.99%.

The invention provides for flexibility with regard to choices of liquidand gas components and compositions. Carriers and detectable substanceswill be chosen based upon their solubility in the liquid used to wet theporous material. There ratio of solubility of the carrier to thedetectable substance may be readily determined by the skilled artisanand may range from about 500:1; about 250:1; about 100:1 about 80:1;about 60:1 about 50:1; about 40:1; about 30:1; about 20:1; about 10:1about 5:1. If the ratio of solubility between the carrier and thedetectable substance is too great; e.g. greater than 1000:1 thedetector, may in some cases become flooded with carrier making thedetection of the detectable substance difficult.

Suitable carriers include compressed air, nitrogen, oxygen, Noble gases,e.g., helium, neon, argon, krypton, xenon, radon, alkanes, e.g.,methane, ethane, propane and the like. Suitable detectable substancesmay include fluoro carbons such as Freon, e.g. C₂F₆, alcohol, sulfurhexafluoride, helium, alkanes, e.g., methane, ethane propane etc.,olefins, e.g. ethylene, propylene, butylenes etc., carbon dioxide,carbon monoxide, hydrogen, volatile organic liquid vapors, e.g.,methanol, ethanol, acetone etc. The skilled artisan will appreciate thatsensitivity of the integrity test will be influenced by the detectorcapability and the rate at which diffusion begins to occur.

In some embodiments, e.g., where the carrier and detectable substanceare both gases, it is useful to choose gas pairs with moderatedifferences in permeability and gas compositions that have one speciesin trace concentration (i.e. the detectable substance) and the otherpresent as the bulk species (i.e. the carrier). In the limit of using adilute tracer gas, the sensitivity of the gas measurement is a functionof the feed composition and φ, the ratio of permeability of one gas (i)to another (j).

$\Phi = \frac{D_{i}S_{i}}{D_{j}S_{j}}$

For example, φ can vary from approximately 0.001 to 1 for binary gasmixtures using common species such as nitrogen, oxygen, carbon dioxide,helium, hydrogen, and hexafluoroethane, with water as the pore-fillingliquid. For tests where the wetting liquid is a hydrophobic liquid, suchas dodecane, gas pairs could include high permeability gases such asethane, propane, and butane paired with low-permeability gases such ashelium, hydrogen, and nitrogen.

In some embodiments at least one of the gases is a hexafluoroethane. Inother embodiments at least one of the gases is a noble gas. In stillother embodiments at least one of the gases is CO₂. In furtherembodiments at least one of the gases is comprised of a mixture ofgases, e.g. air. Where the gases are provided as a mixture of more thanone gas, the mixture may be premixed before being contacted with theporous material. Wide ranges of gas composition are available; forexample feed gas mixtures of hexafluoroethane in CO₂ can vary from lessthan 0.1% to more than 99.9%. The skilled artisan will be able to chooseappropriate gases and gas mixtures based upon known properties such assolubility or permeability in the wetting liquid.

Apparatus and Systems

In certain embodiments the invention provides an apparatus suitable fordetermining the integrity of a porous material. An example of anapparatus suitable for use in the methods of the invention is shown inschematic form in FIG. 1 a. The apparatus may comprise a) a housingsuitable for receiving a porous material to be integrity tested; b) asource of a detectable substance in fluid communication with thehousing; c) a source of a carrier for the detectable substance in fluidcommunication with the housing; d) a detector for detecting thedetectable substance; e) a recirculation pump in communication with thedetector and the housing for containing the porous material; and f) oneor more sources of external force.

The detector may be any commercially available detector suitable fordetecting the detectable substance, e.g., a tracer gas or vapor. Thedetector need not be custom made as required by previously describedphoto acoustic detection methods. The detector may be, for example,Fourier Transform Infra-Red Spectroscopy, mass spectroscopy, gaschromatography.

The external energy source may include any compressed gas, such ascompressed nitrogen, compressed air. Alternatively the external energysource may include a vacuum pump or a combination of one or more sourcesof compressed air and one or more vacuum pumps. A combination ofexternal energy sources, e.g. one or more pumps and one or more sourcesof compressed gas are also contemplated.

The apparatus may comprise one or more valves, e.g. two valves, threeway valves and the like, to control the flow of the carrier and or thedetectable substance, e.g. to the sample contained in the housing, tothe detector, and or to the recirculation pump. One or more valves mayalso be used to control exposure of the sample to an external force. Oneor more valves may be used to control the flow of the carrier anddetectable substance such that the porous material may be tested forintegrity from more than one orientation. Thus where the test isperformed on a membrane, valves may control the flow of the carrier anddetectable substance such that the permeate is found on either the tightside of membrane or the open side of the membrane. Similarly embodimentsof the invention contemplate detecting the permeate on either theskinned surface of the membrane or the skinless surface of the membrane.

Referring to FIG. 1 a, the apparatus comprises a housing (201) forreceiving a sample to be integrity tested, e.g. a membrane cartridge.The housing may comprise a head having one or more ports and a hollowtube which contacts the housing head and extends into the body of thehousing in a direction running parallel to a housing wall. The hollowtube may be suitable for transporting gas into or out of the housing.The housing may be in fluid communication with a gas source (TK-201) andwith a detector and a recirculation pump (PU-201). Positioned betweenthe gas source and the housing, and between the housing and both thedetector and the recirculation pump (PU-201) the apparatus may compriseone or more valves for controlling the flow of gas. The apparatus maycomprise a series of three way valves (FV 220; FV 221, FV 222) whichcontrol the flow of gas into and out of the housing such that the samplemembrane, e.g. a cartridge, may be integrity tested from either surfaceof the cartridge without the need to physically manipulate the samplemembrane once it is positioned in the housing.

Referring to FIG. 1 b, a cross section of a portion of the apparatus ofFIG. 1 a is shown including a housing head (300), a membrane cartridgeinterior support sleeve (301) extending from the housing head andsuitable for receiving a sample membrane; a sample membrane forintegrity testing (302); a hollow tube (303); a plastic filler which mayreduce the open interior volume of the housing thereby facilitating morerapid detection of the detectable substance, e.g. tracer gas; a housingbowl (305) suitable for receiving a sample membrane; a breaking cylinder(306) for holding the membrane sample in place.

FIG. 1 c shows an alternate cross sectional view of the housing head,the membrane cartridge interior support sleeve and the housing frame. Inthis view four ports (307, 308, 309, and 310) are shown all of whichserve to communicate with the exterior of the housing bowl and theinterior of the membrane cartridge thus providing communication with thegas source, the detector and the recirculation pump. FIG. 1 d providesyet another view of the housing head (300) including ports (307, 308 and310); the membrane sample (302); the housing bowl (305); and thebreaking cylinder (306).

In one embodiment, where the sample is a wetted membrane cartridge, thesample may have a first surface facing outward toward the exterior ofthe housing and a second surface facing inward toward the hollow tube.Gas may flow under pressure, from the gas source (201) through three wayvalve (FV220) into the housing through port (307) such that it contactsa first surface of a membrane having a surface facing the exterior ofthe housing. The gas may permeate through the wetted membrane sample,i.e. to the permeate side of the membrane, and flow through the hollowtube (303) and exit the housing via port (308) in communication withthree way valve (FV221), which is in communication with the detector.The gas may enter the detector via a first detector port incommunication with three way valve (FV221), and exit the detector via asecond detector port which is in communication with the recirculationpump (PU-201). The recirculation pump may be in communication with threeway valve (FV222) such that the gas circulates back to the housing andre-enters the housing through port (309) in communication with three wayvalve (FV 222) and the hollow tube on the permeate side of the samplemembrane. The recirculated gas may thus be made available once again tothe detector via the pathway described above.

In another embodiment the apparatus may be used to test a porousmaterial, e.g. a membrane cartridge in the reverse orientation asdescribed above, such that the membrane surface described above as thepermeate side, now becomes the surface first contacted by the gas andthe membrane surface described above as the first surface now becomesthe permeate side. The change in orientation is accomplished by alteringthe flow of gas through a plurality of three way valves. In thisembodiment gas will flow under pressure from the gas source through athree valve (FV 220), but will be diverted to a port (308) incommunication with the inner portion of the membrane sample. The gas maypermeate through the membrane sample into the space between the housingand the sample membrane and will flow out of the housing through a port(310) in communication with three way valve FV 221. Three way valve 221,which is in communication with the detector, transports the gas througha first detector port into the detector. The gas may exit the detectorvia a second detector port in communication with the recirculation pumpPU-201. The gas may enter the recirculation pump via a first port andexit via second port which is in communication with three way valve(FV222) which is in communication with a port situated near the bottomof the housing (FIG. 1 a) such that the recirculated gas is deliveredback to the permeate side of the membrane, i.e. the membrane side facingthe housing wall, such that it is available once again to the detectorvia the pathway described above.

EXAMPLES Example 1 Integrity Testing of Porous Materials withRecirculation of Detectable Gas

Porous membranes were integrity tested using an apparatus similar to theone shown in FIG. 1, except that the apparatus was not configured with aplurality of three way valves. The following protocol was used. Amembrane cartridge was wetted using an appropriate liquid for theparticular type of membrane. The cartridge was installed in the filterhousing which was connected to an FTIR sensor, a recirculation pump, avacuum pump, and a plurality of valves.

The process of testing a cartridge, using a Programmable LogicController, pressure tranducers, and automate valves, was as follows:

1. The recirculation pump was turned on and the system was evacuated tobelow a set vacuum level (pressure sensors PT 203 & 204 below −10 PSIG)using a Venturi vacuum generator (Vaccon, Medfield, Mass.).2. Recirculation of the permeate side volume was continued for 10seconds. The FTIR signal was checked to ensure that it was below asetpoint threshold (44 ppmv C₂F₆). The FTIR background signal afterseveral clean up cycles was used to determine the set point. If thelevel was below the threshold and permeate side was to be set atatmosphere, step 4 was implemented; if initial permeate side testpressure was to be under vacuum step 5 was implemented. If the TracerGas level (i.e. detectable substance) was above the threshold, step 3was implemented.3. Both sides of cartridge were pressurized with nitrogen or compressedair to a set point pressure (1 psig). PT-203 and PT-204 were monitored.When both were above the set point 10 seconds were allowed to elapse,and then Step 1 was repeated.4. Both sides of the filter were brought up to 0 PSIG (14.696 PSIA) withnitrogen or compressed air. Both PT-203 and PT-204 were monitored. Whenboth reached 0 psig (+/−) Step 5 was implemented.5. Tracer Gas was dosed on the upstream side to a partial pressure setpoint of 15.5 PSIG. When PT-203 indicated that the pressure was at setpoint, step 6 was immediately implemented. The skilled artisan will alsoappreciate that while dosing was done instantly, dosing also could havebeen done using a ramp rate (i.e. psi/second). Ramping may provideseveral advantages. A slow ramp could potentially allow recognition of agross defect before putting in the full amount of tracer. It could alsoprovide for a more reproducible set point pressure. Another advantagerelates to detecting defects in pleated membranes. Certain defects onthe pleat peaks may in some cases get pinched off under highdifferential pressure—a slow ramp may eliminate this blinding effect6. The upstream was pressurized to the final set point differentialpressure with nitrogen or compressed air. The differential pressurebetween PT-203 and PT-204 was monitored. When the differential reachedthe set point, step 7 was implemented. Pressurization was done instantlybut could also have been done using a recipe set ramp rate (i.e.psi/second).7. The FTIR signal versus time was monitored. If any of the followingoccurred step 8 was implemented, otherwise signal versus time wasmonitored continually until the set point time elapsed:a. PT-204 was above recipe overpressure set point which could signify agross leak;b. The FTIR signal was above the set point value also signifying a grossleak;c. The time on the recipe test timer expired. Typically the timer rangedfrom 60 to 120 seconds.8. The downstream/permeate side of the filter was evacuated. Thisincluded the FTIR sensor and the recirculation pump, which wereevacuated to exhaust. PT-204 was monitored and a 20 second timer was setwhen the pressure is below recipe set point (−10 PSIG).9. The upstream side of the membrane cartridge was evacuated to exhaust.PT-203 was monitored and 20 second timer was set when pressure was belowrecipe set point (−10 psig). Proceed to step 10 when timer expires.10. The upstream side of the membrane cartridge was pressurized withnitrogen or compressed air to recipe set point (30 psig). PT-203 wasmonitored and a 5 second timer was set when the pressure was above theset point. When the timer was done, step 11 was implemented, unless theclean up cycle counter (recipe set point for number of cycles—wasonly 1) was complete, then step 12 was performed.11. The upstream side of the membrane cartridge was evacuated toexhaust. PT-203 was monitored. A 10 second timer was set when thepressure was below the set point (−10 psig). An increment clean upcounter was used to keep track of how many cycles of pressurization withcarrier gas followed by evacuation was performed. As stated above, inthis experiment one cycle was done. When the timer was done, step 10 wasrepeated.12. The filter drain valve was opened and vented downstream of thefilter. Monitor PT-203 and PT-204 were monitored. When PT-203 and PT-204both reached 0 PSIG (+/−)10 second timer was set. When timer was donethe test was complete.

Example 2 Comparison of FTIR Signal in Membrane with Known Defects

Individual good cartridges were tested in conjunction with a series offixed orifices of a know diameter. To provide a standard for comparison,a plug was inserted in the orifice holder to eliminate the effects ofthe known defect. A series of tests with the same cartridge wereperformed with each cartridge tested having a single defect of knowndiameter. The cartridge used was a 10 inch 0.22 micron hydrophillic PVDFDurapore® (Millipore Corporation, Billerica, Mass.) membrane cartridgesubassembly. The results are shown in FIG. 2 and demonstrate distinctcurves for defects of differing sizes. The test conditions were 25% (byvolume) C₂F₆ 75% compressed air, with a trans membrane pressuredifference of 46 psi. The unit of time in FIG. 2 is seconds, while theunit for C₂F₆ concentration is parts per million (ppm) (by volume). Thesensor used is a MKS InDuct FTIR (MKS Instruments, Wilmington, Mass.)with a lower detection limit of 1 ppmv C₂F₆.

A theoretical concentration of C₂F₆ versus time was also calculatedassuming choke flow for individual membranes having a defect of knownsize. FIG. 3 shows a comparison of the calculated values and theexperimental results obtained using fixed orifice defects.

Example 3 Integrity Testing of Process Sub-Assembly Cartridges

Integrity testing was performed on 48 production units of 10″ processsub assembly cartridges with a 0.22 micron hydrophillic PVDF Durapore®(Millipore Corporation, Billerica, Mass.) membrane. The units weretested both prior to and post gamma irradiation. The test conditionswere as reported above in Example 2. The results are shown in FIGS. 4 a(pre gamma irradiation) and 4 b (post gamma irradiation). Afterintegrity testing using FTIR detection, according to one embodiment ofthe invention, the same units were subjected to testing with PLATO(photo acoustic detection) (U.S. Pat. No. 5,581,017), and an existingproduction mass flowrate test (diffusion test) (Millipore Catalog 94-95,Millipore Corporation, Billerica Mass.). A functional bacterialretention test was also performed. A comparison of these results isshown in Table 1. (“?” indicates an indeterminate result). The resultsfrom FIG. 4 b (a known good cartridge with a 1.31 micron defect) wasconsidered as the cutoff for a defective membrane. The integrity testdescribed herein demonstrated good sensitivity under the conditionstested.

TABLE 1 FTIR Results: Slope Time to reach (ppm Freon Retention Cartridge245 ppm C₂F₆ C₂F₆/ Diffusion Results ID (seconds) second) PLATO (sccm)(counts) 1081 5 86.7 BAD DK TNTC 1108 7 107 BAD DK TNTC 1092 15 18.9 BAD0.58 TNTC 1395 20 13.8 BAD 0.57 TNTC 1097 22 17.1 BAD 0.9 TNTC 1336 3114.3 BAD 0.47 TNTC 1291 27 9.8 BAD 0.39 TNTC 1078 35 8.7 ? 0.33 TNTC1094 109 2.2 GOOD 0.19 3, 4 1088 >120 0.38 GOOD 0.15 0 1103 >120 0.14GOOD 0.16 0 1407 >120 0.24 GOOD 0.23 0 1196 >120 0.28 GOOD 0.29 01181 >120 0.51 GOOD 0.3 0 1109 >120 0.35 GOOD 0.17 0 1349 >120 0.31 GOOD0.29 0 1293 >120 0.17 GOOD 0.17 NOT 1398 >120 0.34 GOOD 0.21 TESTED1360 >120 0.25 GOOD 0.24 1373 >120 0.35 GOOD 0.33 1191 >120 0.38 GOOD0.23The cut off for a defective membrane using an existing production massflowrate test was 0.47 standard cubic centimeters per minute (sccm).

Example 4 Reproducibility of Integrity Test Results

In order to demonstrate that the integrity test described hereinprovides reproducible results replicate tests were performed on a knowngood membrane cartridge tested as is or with a fixed orifice defect ofknown size. The cartridge was comprised of a PVDF Durapore® membrane(Millipore Corp., Billerica, Mass.) and test conditions included usingFreon (15.5 psi) as the detectable substance. The system was operated ata pressure differential of 46 psid. FIG. 5 shows the results of 10replicate tests of a known good cartridge having a deliberately placed1.31 micron orifice defect. The measured FTIR signal slope of the tenruns has an average of 2.90 ppmv C₂F₆/sec) with a standard deviation of0.20 ppmv C₂F₆/sec. For comparison, multiple runs with the same filteralone (no defect) are shown for comparison.

Example 5 Integrity Testing of Asymmetric Membranes

Asymmetric membranes were integrity tested according to one embodimentof the invention. It was discovered that the test sensitivity may insome cases be affected by the background diffusion of the tracer gasthrough the integral membrane. Thus, different membranes may havedifferent optimal test conditions (including gas/vapor mixtures) andlimits of detection. FIGS. 6 and 7, show the results obtained whendevices containing a thin, asymmetric membrane were tested with varioussize orifices (i.e. intentionally placed defects). When these membraneswere tested using the conditions developed for the Gamma Durapore® (100to 150 micron thick symmetric structure), the limit of detection wassomewhere between 5 and 10 microns. When the test was performed in thereverse direction such that the gas mixture contacted the tight side ofthe membrane first, (to minimize water layer thinning of the asymmetricstructure) and at a lower differential pressure (30 psig vs 46 psig),the detection limit was lowered to between 2 and 5 microns.

Many modifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only and are not meant to be limiting in anyway. It is intended that the specification and examples be considered asexemplary only, with a true scope and spirit of the invention beingindicated indicated by the following claims

21. A method of assessing the integrity of a porous material withoutallowing the method to reach a steady state comprising a) wetting theporous material with water; b) contacting a first surface of the porousmaterial with a mixture comprising a carrier and a detectable substance;c) applying pressure to the first surface of the porous material suchthat at least some of the carrier and the detectable substance permeatethe porous material; d) recirculating the carrier and detectablesubstance found in a permeate of the porous material in a fixed volumeon the permeate side while continuing to apply the pressure of (c); e)assessing the concentration of the detectable substance in the permeateof the porous material over time; and f) comparing the assessedconcentration in (e) with the concentration of the detectable substancein a permeate of an integral porous material exposed to the sameconditions over time, wherein an assessed concentration in (e) which isgreater than the concentration of the detectable substance in a permeateof the integral porous material indicates the porous material is notintegral.
 22. A method of assessing the integrity of a porous membranewithout allowing the method to reach a steady state using an apparatuscomprising: a) a housing suitable for receiving a porous membrane to beintegrity tested; b) a source of a detectable substance in fluidcommunication with the housing; c) a source of a carrier for thedetectable substance in fluid communication with the housing; d) adetector for detecting the detectable substance; e) a recirculation pumpin communication with the detector and the housing for containing theporous membrane; and f) a source of an external force; wherein themethod of assessing the integrity of the porous material received in thehousing of (a) in the apparatus comprises i) wetting a porous materialwith a liquid; ii) contacting a first surface of the porous membranewith a mixture comprising a source of a detectable substance of (b) anda source of the carrier of (c) for the detectable substance; iii)applying an external force of pressure of (f) to the first surface ofthe porous membrane such that at least some of the carrier and thedetectable substance permeate the porous membrane; iv) recirculating thecarrier and detectable substance found in a permeate of the porousmembrane in a fixed volume on the permeate side by the recirculationpump of (e) while continuing to apply the pressure of (iii); v)assessing the concentration of the detectable substance in the permeateof the porous membrane over time using the detector of (d); vi)comparing the assessed concentration in (iii) with the concentration ofthe detectable substance in a permeate of an integral porous membraneexposed to the same conditions over time, wherein an assessedconcentration in (v) which is greater than the concentration of thedetectable substance in a permeate of the integral porous membraneindicates the porous membrane is not integral.